Cancer is a class of diseases which occurs because cells become immortalised; they fail to heed customary signals to turn off growth which is a normal function of remodelling in the body that requires cells to die on cue. Apoptosis, or programmed cell death, can become defective and when this happens malignant transformation can take place. The immortalised cells grow beyond their normal limits and invade adjacent tissues. The malignant cells may also metastasise and spread to other locations in the body via the bloodstream or lymphatic system. Cancer cells often form a mass known as a tumour.
There are about 200 different types of cancer; the cancers can start in any type of body tissue although many cancers will metastasise into other body tissues. There are many different causes of cancer and these include; carcinogens, age, genetic mutations, immune system problems, diet, weight, lifestyle, environmental factors such as pollutants, some viruses for example the human papilloma virus (HPV) is implicated in cervical cancer and some bacterial infections are also known to cause cancers.
There are many different treatment options for cancer and the treatment sought is often determined by the type and stage of the cancer. Treatment options include; chemotherapeutic drug treatment, hormonal drug treatment, radiotherapy, surgery, complementary therapies and combinations thereof.
Prostate cancer is the most common type of cancer in men and accounts for 24% of all UK male cancers. In 2006 there were over 35,000 new cases of prostate cancer diagnosed in the UK alone.
The prostate is a gland in the male reproductive system and symptoms of cancer in the prostate can include pain, difficulty urinating, problems with sexual intercourse and erectile dysfunction. Prostate cancer may metastasise to the bones and or lymph nodes. Treatment options for prostate cancer include surgery, radiation therapy, chemotherapy and hormone treatment.
Hormone treatment usually involves treatment with an anti-androgen such as cyproterone acetate, flutamide or bicalutamide, either alone or in combination with a chemotherapeutic agent. These treatments work to stop the production of testosterone (androgen) which can slow down tumour growth or even shrink the tumour. While the prostate cancer cells are responding to anti-androgens, they are referred to as ‘hormone-sensitive’ prostate cancer. Unfortunately, after a few years of treatment with anti-androgens the prostate cancer stops responding to hormone treatment and is termed ‘hormone-insensitive’ prostate cancer. At this stage the cancer growth cannot be controlled by the hormone treatment.
In order to test the effectiveness of different compounds in the treatment of either hormone-sensitive or hormone-insensitive prostate cancer two different cell lines can be used. The cell line LNCaP are hormone-sensitive prostate cancer cells which were derived from a supraclavicular lymph node metastasis in a 50 year old male in 1977. The cell line DU-145 are hormone-insensitive prostate cancer cells which were derived from a brain metastasis.
It is known that expression levels of both cannabinoid receptors, CB1 and CB2, were significantly higher in CA-human papillomavirus-10 (virally transformed cells derived from adenocarcinoma of human prostate tissue), and other human prostate cells LNCaP, DU-145, PC3, and CWR22RN1 than in human prostate epithelial and PZ-HPV-7 (virally transformed cells derived from normal human prostate tissue) cells (Sarfaraz, 2005).
Additionally it is known that WIN-55,212-2 (mixed CB1/CB2 agonist) treatment with hormone sensitive LNCaP cells resulted in a dose—(1-10 Mmol/L) and time-dependent (24-48 hours) inhibition of cell growth. Blocking of CB1 and CB2 receptors by their antagonists SR141716 (CB1) and SR144528 (CB2) significantly prevented this effect.
These results suggested that WIN-55,212-2 or other cannabinoid receptor agonists could be developed as novel therapeutic agents for the treatment of prostate cancer.
Cannabis has been ascribed to be both a carcinogen and anti-cancer agent. In particular smoking cannabis is known to be carcinogenic as the cannabis smoke contains at least 50 different known carcinogenic compounds, many of which are the same substances found in smoked tobacco. One of these carcinogens, benzopyrene is known to cause cancer as it alters a gene called p53, which is a tumour suppressor gene. Cannabis contains the substance tetrahydrocannabinol (THC) which has been shown to cause benzopyrene to promote the p53 gene to change.
Researchers however have discovered that some cannabinoids, including THC and cannabidiol (CBD) are able to promote the re-emergence of apoptosis so that some tumours will heed the signals, stop dividing, and die. The process of apoptosis is judged by observation of several phenomena including: reduced cellular volume, condensation of nuclear chromatin, changes in distribution of phospholipids in plasma membrane phospholipids, and cleavage of chromatin into DNA fragments called DNA ladders.
Another method by which tumours grow is by ensuring that they are nourished: they send out signals to promote angiogenesis, the growth of new blood vessels. Cannabinoids may turn off these signals as well.
Cannabinoids have been shown to have an anti-proliferative effect on different cancer cell lines. The cannabinoids THC, THCA, CBD, CBDA, CBG and CBC and the cannabinoid BDS THC and CBD were tested on eight different cell lines including DU-145 (hormone-sensitive prostate cancer), MDA-MB-231 (breast cancer), CaCo-2 (colorectal cancer) and C6 (glioma cells). The data for each cannabinoid in each different type of cancer varied but generally the best data were observed with CBD or CBD BDS. The IC50 values for all the cannabinoids on the DU-145 were quite high inferring that none of the cannabinoids tested were particularly effective in the inhibition of hormone-insensitive prostate cancer (Ligresti, 2006).
Several transient receptor potential (TRP) channels have been implicated in the survival, growth and spread of prostate and other cancers. TRPM8 is expressed in sensory neurons, where it responds to cold and to cooling agents, notably menthol, but it is also abundantly expressed in the prostate. In particular TRPM8 is over-expressed in hormone-sensitive prostate cancer cells, but expression of TRPM8 is almost completely ablated once the cancer becomes hormone-insensitive and in patients receiving anti-androgen therapy. Expression of TRPM8 is stimulated by androgens in hormone-sensitive prostate cancer cell lines (LNCaP). There is evidence that expression of TRPM8 is required for survival of prostate cancer cells.
The mechanism of such an action of TRPM8 is likely to relate to its ability to modulate intracellular calcium, and possibly even the distribution of calcium within the cell. The latter point may be important because of the localisation of TRPM8 in the prostate cancer cell. While found on the cell membrane, it is also found on the endoplasmic reticulum; thus any potential therapeutic agent which targets the TRPM8 receptor must be able to gain good access to the intracellular space.
The endogenous cannabinoid anandamide has been shown to antagonise TRPM8 (De Petrocellis, 2007). The authors also showed that stimulation of CB1 receptors transiently antagonised TRPM8 receptors expressed on the same cells.
The application WO 2008/129258 describes the use of cannabinoid-containing plant extracts in the prevention or treatment of diseases or conditions that are alleviated by blockade of one or more types of TRP channel. Different binding potentials of the cannabinoid-containing plant extracts at the TRPA1 and TRPM8 channels are described. The diseases and conditions to be prevented or treated include: neuropathic pain, inflammation, vasoconstriction or cancer.
The TRPM8 receptor has also been found in breast, colon and skin cancers.
It has been shown that CBD is able to able to down-regulate the expression of the DNA binding protein inhibitor, Id-1 in human breast cancer cells (McAllister, 2007). The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion.
CBD has also been shown to inhibit human cancer cell proliferation and invasion through differential modulation of the ERK and ROS pathways, and that sustained activation of the ERK pathway leads to down-regulation of Id-1 expression. It was also demonstrated that CBD up-regulates the pro-differentiation agent, Id-2. Using a mouse 4T1 cell line and a model of metastatic breast cancer, CBD significantly reduced metastatic spread. As such CBD may represent a promising treatment of breast cancer in patients with secondary tumours (McAllister, 2009).
Recent evidence indicates that CBD is a GPR55 antagonist; this raises the possibility that this receptor may underlie the effects of CBD on breast and other tumour cells. GPR55 couples to G12/13 and the downstream activation of the RhoA, rac1 and cdc42 small GTPases; this pathway is crucial in cytoskeletal reorganisation and cell migration. Increased G12/13 expression has been found in early stage human breast cancer cells taken by biopsy and inhibition of G13 decreases the level of breast cancer cell metastasis in vivo (Kelly et al, 2007).
The anti-proliferative effects of CBD have also been evaluated on U87 and U373 human glioma cell lines, (Massi, 2004). The anti-proliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. In addition CBD, administered s.c. to nude mice at the dose of 0.5 mg/mouse, significantly inhibited the growth of subcutaneously implanted U87 human glioma cells. It was concluded that CBD was able to produce a significant anti-tumour activity both in vitro and in vivo, thus suggesting a possible application of CBD as a chemotherapeutic agent.
The application WO/2006/037981 describes the use of the cannabinoid CBD to prevent tumour cells migrating or metastisising from an area of uncontrolled growth to an area away from the original tumour site. CBD caused a concentration-dependent inhibition of the migration of U87 glioma cells, quantified in a Boyden chamber. Since these cells express both cannabinoid CB1 and CB2 receptors in the membrane, the group also evaluated their engagement in the anti-migratory effect of CBD.
Cannabinoids have been shown to play a fundamental role in the control of cell survival/cell death. It has been reported that cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and non-neural cells, and that cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo (Guzman, 2001).
A pilot clinical study of THC in patients with recurrent glioblastoma multiforme has been conducted. This pilot phase I trial consisted of nine patients with recurrent glioblastoma multiforme who were administered THC intra-tumourally. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. They also evaluated THC action on the length of survival and various tumour-cell parameters. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15-33).
The application WO 2008/144475 describes treating cell proliferation disorders including cancer with cannabidiol derivatives either alone or in combination with THC or a derivative thereof.
The application WO 03/063847 describes the use of CBDA or CBDVA as an active pharmaceutical substance. The focus of the application provides a treatment for nausea, vomiting emesis and motion sickness.
The application WO 2009/147439 describes the use of a combination of cannabinoids, particularly tetrahydrocannabinol (THC) and cannabidiol (CBD), in the manufacture of a medicament for use in the treatment of cancer. In particular the cancer to be treated is a brain tumour, more particularly a glioma; more particularly still a glioblastoma multiforme (GBM).
The application WO 2009/147438 describes the use of one or more cannabinoids, particularly THC and/or CBD in combination with a non-cannabinoid chemotherapeutic agent in the manufacture of a medicament for use in the treatment of cancer. In particular the cancer to be treated is a brain tumour, more particularly a glioma, more particularly still a glioblastoma multiforme (GBM). The non-cannabinoid chemotherapeutic agent may be a selective estrogen receptor modulator or an alkylating agent.
The literature and corresponding patent applications demonstrate the general usefulness of cannabinoids in the area of cancer research and treatment.
It is an object of the present invention to find improved and/or alternative cancer therapies. To this end a platform of data representing the use of isolated phytocannabinoids and phytocannabinoid botanical drug substances (BDS) in different aspects of the treatment of cancer is provided and the results extrapolated to identify groups of phytocannabinoids, whether isolated or in the form of a BDS, which appear more promising than others in specific treatments.